Open AccessHypoxia-inducible factors individually facilitate inflammatory myeloid metabolism and inefficient cardiac repair
Author(s) -
Matthew DeBerge,
Connor Lantz,
Shirley Dehn,
David P. Sullivan,
A.M. van der Laan,
Hans W.M. Niessen,
Margaret E. Flanagan,
Daniel J. Brat,
Matthew J. Feinstein,
Sunjay Kaushal,
Lisa D. Wilsbacher,
Edward B. Thorp
Publication year - 2021
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20200667
Subject(s) - hypoxia inducible factors , myeloid , hypoxia (environmental) , proinflammatory cytokine , cancer research , microbiology and biotechnology , hif1a , mitochondrial biogenesis , biology , inflammation , medicine , immunology , mitochondrion , chemistry , angiogenesis , biochemistry , organic chemistry , oxygen , gene
Hypoxia-inducible factors (HIFs) are activated in parenchymal cells in response to low oxygen and as such have been proposed as therapeutic targets during hypoxic insult, including myocardial infarction (MI). HIFs are also activated within macrophages, which orchestrate the tissue repair response. Although isoform-specific therapeutics are in development for cardiac ischemic injury, surprisingly, the unique role of myeloid HIFs, and particularly HIF-2α, is unknown. Using a murine model of myocardial infarction and mice with conditional genetic loss and gain of function, we uncovered unique proinflammatory roles for myeloid cell expression of HIF-1α and HIF-2α during MI. We found that HIF-2α suppressed anti-inflammatory macrophage mitochondrial metabolism, while HIF-1α promoted cleavage of cardioprotective MerTK through glycolytic reprogramming of macrophages. Unexpectedly, combinatorial loss of both myeloid HIF-1α and HIF-2α was catastrophic and led to macrophage necroptosis, impaired fibrogenesis, and cardiac rupture. These findings support a strategy for selective inhibition of macrophage HIF isoforms and promotion of anti-inflammatory mitochondrial metabolism during ischemic tissue repair.